Cardiac Electrophysiology I

Question 1

Resting Cardiac Muscle Cell

Answer 1

• biophysicists look at the cell from the inside with intracellular electrodes
• electrocardiologists look at the cell from the outside with extracellular electtrodes

Question 2

Equilibrium potential

Answer 2

• voltage obtained for a given concentration gradient of a single ion at equilibrium across a semi-permeable membrane
• the equilibrium potential refers to a given single ion and is represented by the Nernst equilibrium equation

Question 3

Gibbs Donnan equilibrium

Answer 3

• a special kind of equilibrium involving impermeable polyelectrolyte on one side of a membrane that is permeable to salts but impermeable to the polyelectrolyte
• exist across capillary membranes if albumin and other charged plasma proteins are in the blood but not in the interstitial fluid
• results in an unequal distribution of salts across the membrane and a slight membrane potential that has the same sign as the charge on the polyelectrolyte

Question 4

Diffusion potentials

Answer 4

• when two or more ions are permeable to a membrane but the various ions have differing permeabilities
• calculated by the Goldman Hodgkin Katz equation

Question 5

Epithelial membrane potentials

Answer 5

-are the differences of electrical potential that occur between two dilute solutions when the membrane itself is a layer of cells, such as occurs in the kidney and gastrointestinal systems

Question 6

Equilibrium potential for specific ion

Answer 6

-Na+ +60 mV
-K+ -90 mV
-Ca++ +120mV
z= 1 for Na+ and K+, but is 2 for Ca++
-voltage gated Na+, K+, and Ca++ channel share a similar tetrameric molecular structure with each subunit of the tetramer consisting of six helical segments

Question 7

Nernst Equilibrium Potential for K+

Answer 7

= -58 log ([Kin]/[Kex])

• raising Kex decreases outward K+ gradient and makes Ek less negative (more positive) which is depolarizing
• raising Kin increases outward K+ gradient and makes Ek more negative, which is hyperpolarizing
• at the low external K+, the membrane potential is more positive than predicted by the Nerst equation
• depolarization- means more positive
• hyperpolarization- means more negative

Question 8

GHK Diffusion Potential

Answer 8

• Raising K(in) increases outward K+ gradient and makes Em more negative inside which is hyperpolarizing
• Raising K(ex) decreases outward K+ gradient and makes Em less negative (more positive) inside, which is depolarizing
• Raising Na(in) decreases inward Na+ gradient and makes Em less positive (more negative) inside, which is hyperpolarizing
• Raising N(ex) increasing inward Na+ gradient and makes Em more positive inside which is depolarizing

Question 9

Biological Diversity of Cell Membrane Diffusion

Answer 9

• Neuron -70mV
• Skeletal Muscle -85mV
• Cardiac Muscle
• Atrial and Ventricular -80mV
• AV Node -65mV
• SA Node -55mV
• Smooth Muscle -55mV
• Secretory Cell -55mV
• Human Red Blood Cell -11mV
• the relative permeability of sodium to potassium determine cell resting potentials

Question 10

Outward rectification

Answer 10

-the conductance of outward currents is greater than for inward currents, and the current voltage curve slopes upward nonlinearly

Question 11

Inward rectification

Answer 11

• the conductance of inward currents is greater than for outward currents and the current/voltage plots slope downward nonlinearly
• K+ channel is inward rectifier
• when the cell is hyperpolarized at rest, the conductance of this channel is high, however upon depolarization during the upstroke of an action potential, the conductance of the iK1 channel becomes considerably less, allowing the inward sodium current to depolarize the membrane potential
• at normal resting potential, the inward rectifier channel iK1 mediates a positive efflux of potassium

Question 12

Molecular structure of K channel

Answer 12

• 4 identical subunits
• the transmembrane domain forms the pore that allows the ions to cross the membrane
• the selectivity filter filters out ions other than K

Question 13

Single File Electrodiffusion Through an Open Channel

Answer 13

-ions move through open channels by the process of electrodiffusion in single file, three K+ ions may simultaneously occupy a K channel but the ions do not pass each other in transit

Question 14

Channel blockers

Answer 14

• like Ca++ channel blockers occlude the calcium channel at the extracellular side
• Calcium channel blockers can reduce the heart rate and contractility of the heart resulting in lower cardiac output and lower blood pressure
• ACE inhibitors blocking the conversion of angiotensin I to angiotensin II are also widely used to relax smooth muscle resulting in decreased TPR and lower blood pressure

Question 15

How Membrane Voltage Changes when channels open

Answer 15

• whenever a cell becomes more permeable to an ion, the effect upon the cell’s membrane voltage is to bring it closer to the equilibrium potential of that particular ion
• when a cardiac muscle cell at Vm = -60 mV suddnely becomes very permeable to Na+, what will happen
• Ina increases greatly as Na+ flows into the cell
• the value of Vm readily moves toward +60 mV the value of Ena causing the depolarizing upstroke of the AP

Question 16

Overshoot

Answer 16

• the upstroke goes beyond zero to positive potentials
• during depolarization is strong evidence that an inwardly directed positive ion gradient (Na+) rather than an outwardly directly positive ion gradient (K+) is now dominating

Question 17

Sodium and Calcium channels

Answer 17

• positively charged domain serves as voltage sensor- causing activation of channel
• outwardly rectifying- their conductances are low at hyperpolarized, inward positive currents are low at rest but they open up at a threshold level of membrane depolarization and acquire a much larger conductance that enables positive inward currents during the upstroke of action potential
• following activation Na channels go to inactivated sate- lid of trash can
• inactivation of Ca is slower than Na
• they then go back to resting state with the m-gate closed and the h-gate open

Question 18

Refractory periods

Answer 18

• absolute- defined as the time during which an AP cannot be initiated , no matter how strong is the magnitude of the stimulus, the inactivation gates are still closed
• relative- time during which a normal stimulus does not initiate an AP but raising the magnitude does result in an AP
• refractory of heart occurs during diastole- allowing time for heart to refill before next contraction

Question 19

Low membrane potential reduces rate of depolarization

Answer 19

• degree of inactivation can influence size of AP
• if resting potential is more depolarized than usual some channels will be in inactivated state so the AP is smaller and slower upstroke

Question 20

Speed at which threshold is reached

Answer 20

-a stimulus reaching threshold slowly results in an AP with a slower rate of depolarization and smaller amplitude

Question 21

Voltage-gated activation of outwardly rectifying K+ channels

Answer 21

• charged transmembrane domains move when the transmembrane voltage becomes more positive
• this level causes a change in conformation of the channel pore, thereby opening the channel
• the conductance is higher at depolarized than at hyperpolarized voltages and the currents are outward for K+ channel

Question 22

Evolution of Channel Proteins

Answer 22

• there are a variety of different channel proteins, not just one type
• more sub-types of potassium than anything else
• possibly Na came from Calcium channels
• different cells have different sub-types of the major ion channels and within the same cell, more than a few sub-types of the same ion channel may co-exist with their separate voltage and time dependencies and individual rectification properties, molding the AP to an optimal functional shape in accordance with cell function

Question 23

Delayed Outward Rectified K+ Channel

Answer 23

• in muscle and nerve it is responsible for repolarization phase of AP
• activates upon depolarization with time delay
• outward rectifying = a much larger conductance at positive depolarized voltages than at negative hyperpolarized voltages
• ball and chain mechanism: peptide on B-subunit inactivates, it can be cleaved off by proteolytic enzyme so that the channel stays open

Question 24

Model of Ion Channel Gating

Answer 24

• ion channels have specific domains that function as selectivity filters determining which ion will permeate through the channel
• other domains: voltage sensors that open the activation gates (m gates), increasing conductance
• some have inactivation gates (h gates)
• open channel= ion permeation via electrodiffusion
• voltage moves toward the equilibrium potential of the most conductive ion

Question 25

Cardiac Potentials in different regions of the heart

Answer 25

• AP in the atrium, bundle of His, Purkinje network and ventricles have APs involving sodium dependent upstokes, calcium dependent plateaus and K dependent repolarization
• SA node- pacemaker potentials have smaller Ca dependent upstrokes and K dependent repolarizations (No Na), also has a spontaneously depolarizing ramp depolarization (automatic)
• similar for AV node

Question 26

Skeletal Muscle vs Cardiac Muscle AP

Answer 26

• the duration of skeletal muscle AP is only a few msec where cardiac AP have a plateau 300-400msec
• phases 1 and 2 of cardiac muscle APs do not have clear counterparts in nerve and skeletal muscle. Repolarization is monophasic for skeletal but triphasic for cardiac

Question 27

Ionic Currents for Purkinje Fiber AP

Answer 27

• resting -90mv
• overshoot can reach +30 mV (amplitude >120 mv)
• low internal resistance favors rapid propagation velocity in the His-Purkinje system
• long duration (>300 msec) with a correspondingly long refractory period prevents ventricular muscle adjacent to His-Purkinje system from re-activating the conduction system
• membrane conductance high early phase but falls the end of this phase of AP

Question 28

Phases of AP

Answer 28

0- Upstroke; fast inward sodium current that rapidly inactivates (iNa)
1- Transient repolarization; transient outward K current (ito1, ito2)
2-Plateau; slow outward K currents (iKr, iKs, iKCa) and slow inward L-Type calcium current (iCaL) that all slowly inactivate
3- Repolarization; delayed outward rectifer K currents (iKr and iKs). iKr is rapid, iKs is slow activating
4- Resting Potential; inward rectifier K currents (iK1)

• sodium channels open the first wave of depolarization, than depolarized enough (more positive) for L type Calcium channels
• T-type calcium important to contributing to the generation of pacemaker currents in SA node